PT  - JOURNAL ARTICLE
AU  - Synofzik, Matthis
AU  - Schicks, Julia
AU  - Lindig, Tobias
AU  - Biskup, Saskia
AU  - Schmidt, Thorsten
AU  - Hansel, Jochen
AU  - Lehmann-Horn, Frank
AU  - Schöls, Ludger
TI  - Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous <em>DARS2</em> mutation
AID  - 10.1136/jmg.2011.090282
DP  - 2011 Oct 01
TA  - Journal of Medical Genetics
PG  - 713--715
VI  - 48
IP  - 10
4099  - http://jmg.bmj.com/content/48/10/713.short
4100  - http://jmg.bmj.com/content/48/10/713.full
SO  - J Med Genet2011 Oct 01; 48
AB  - Background Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2, and drug treatments have remained elusive.Methods Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions.Results The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL.Conclusions This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2-associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2-mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.